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Camptothecin-analog with a novel, flipped lactone-stable, E-ring and methods for making and using same

A technology of camptothecin and its analogs, applied in the field of "triggering" E-ring camptothecin, which can solve the problems of CPT not suitable for direct clinical use, poor water solubility, etc.

Inactive Publication Date: 2009-07-08
BIONUMERIK PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition to the aforementioned toxicity and limited clinical response to CPT as previously described, CPT is also considered unsuitable for direct clinical use due to poor water solubility

Method used

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  • Camptothecin-analog with a novel, flipped lactone-stable, E-ring and methods for making and using same
  • Camptothecin-analog with a novel, flipped lactone-stable, E-ring and methods for making and using same
  • Camptothecin-analog with a novel, flipped lactone-stable, E-ring and methods for making and using same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment I

[0390] For injection or infusion into aqueous body fluids, the formulation contains a total dose of about 0.1 mg / day dissolved in 1 to 10 parts of N-methylpyrrolidone, dimethylacetamide and / or dimethylisosorbide in an acidified vehicle. m 2 to about 100mg / m 2 Novel lactone-stabilized "trigger" E-ring camptothecin, acidified carrier comprising about 10 to about 40 percent acceptable alcohol, about 4 to about 10 parts by weight polyether polyol and about 1 to about 10 parts non- ionic surfactant. Suitable alcohols include dehydrated ethanol, benzyl alcohol. Suitable polyether polyols include polyethylene glycol 200, polyethylene glycol 300, propylene glycol. Suitable nonionic surfactants include, but are not limited to, polysorbate 80. In a preferred embodiment, the novel lactone-stabilized "trigger" E-camptothecin formulation is provided as an intravenous injectable in a 1 mg vial containing a sterile non-aqueous solution of the drug in a carrier, in The acidified medium a...

Embodiment II

[0392] The second formulation contained a total dose of approximately 0.1 mg / m in an acidified vehicle 2 to about 100mg / m 2 The new lactone-stabilized "trigger" E-ring camptothecin, acidifying vehicle comprises about 0.1 to 2 parts alcohol and about 1 to 10 parts nonionic surfactant. Suitable alcohols include ethanol dehydrate USP and benzyl alcohol. Suitable nonionic surfactants include polyoxyethylated oils, such as polyoxyethylated vegetable oils, such as castor oil, peanut oil and olive oil. In a preferred embodiment, 1 mg to 200 mg of the novel lactone-stabilized "trigger" E-camptothecin is formulated in 1 to 10 parts of N-methylpyrrolidone, dimethylisosorbide and / or dimethyl Acetamide, 1 to 10 parts of CremaphorEL TM (polyoxyethylated castor oil), 0.1 to 2 parts by weight of dehydrated ethanol USP and 0.1 to 0.9 parts of citric acid to adjust the final pH to 3 to 4.

Embodiment III

[0394] Oral formulation of new lactone-stabilized "trigger" E-cyclamptothecin in soft gelatin capsules (e.g., composed of gelatin / glycerin / sorbitol / scavenging agent) at 1 to 10 parts of N-methylpyrrolidone, di 1.0 parts of the new lactone-stabilized "trigger" E-cyclamptothecin in methylisosorbide and / or dimethylacetamide, 0.1 to 0.5 parts by weight citric acid, 1 to 10 parts by weight glycerol and 5 to 9 Parts by weight of polyethylene glycol 200 to 300, total solution weight 0.2 to 2 parts by weight of dehydrated ethanol, 0.05 to 0.5 parts by weight of sodium acetate, using 0.05 to 1.0 parts by weight of pluronic poloxamer and 2 to 10 parts by weight of bovine Sulfocholic acid. Soft gelatin capsules may also be composed of any of a variety of mixtures useful for this purpose including, for example, mixtures of gelatin, glycerin, sorbitol and parabens.

[0395] It should be noted that in order to prolong the stability and solubility of the new lactone-stabilized "trigger" E-c...

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Abstract

The present invention discloses: (i) a novel, lactone-stable, ''flipped'' E-ring camptothecin, pharmaceutically-acceptable salts, and / or analogs thereof; (ii) methods of synthesis of said novel, lactone-stable, ''flipped'' E-ring camptothecin, pharmaceutically-acceptable salts, and / or analogs thereof; (iii) pharmaceutically-acceptable formulations comprising said novel, lactone-stable, ''flipped'' E-ring camptothecin, pharmaceutically-acceptable salts, and / or analogs thereof, and, optionally, one or more additional chemotherapeutic agents; (iv) methods of administration of said novel, lactone-stable, ''flipped'' E-ring camptothecin, pharmaceutically-acceptable salts, and / or analogs thereof, and, optionally, one or more additional chemotherapeutic agents, to subjects in need thereof; and (v) devices for the administration of said novel, lactone-stable, ''flipped'' E-ring camptothecin, pharmaceutically-acceptable salts, and / or analogs thereof, and, optionally, one or more chemotherapeutic agents, to subjects in need thereof.

Description

field of invention [0001] The present invention relates to: (i) novel lactone-stabilized "flipped" E-camptothecins, pharmaceutically acceptable salts and / or analogs thereof; (ii) said novel lactone-stabilized "trigger" E-camptothecin, a pharmaceutically acceptable salt thereof and / or a synthetic method of an analog; (iii) "trigger" E-camptothecin containing said new lactone stabilization, A pharmaceutically acceptable salt and / or analog thereof, and optionally a pharmaceutically acceptable formulation of one or more other chemotherapeutic agents; (iv) a "trigger" that stabilizes the new lactone E - a method of administering cyclocamptothecin, a pharmaceutically acceptable salt and / or analog thereof, and optionally one or more other chemotherapeutic agents to a patient in need; and (v) for administering said novel A device for administering a lactone-stabilized "trigger" E-ring camptothecin, a pharmaceutically acceptable salt and / or analog thereof, and optionally one or more o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4745C07D491/22
CPCC07D491/22A61P35/00
Inventor F·H·豪歇尔
Owner BIONUMERIK PHARMA INC
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